Pulmonary macrophages may be the most important primary defense system protecting the lungs from microbial invasions and inhaled pollutants, as well as from neoplastic growth. They may also play a significant role in the pathogenesis of chronic inflammation and autoimmune disease processes. Since germ-free, colostrum-deprived, immunologically "virgin" piglets have absolutely no "resident" pulmonary alveolar macrophages (PAM) at birth, this model provides a unique opportunity to investigate the following five specific aims: (1)\ontogenic development and differentiation of "resident" PAM in a controlled environment starting from the zero level; (2)\characterization of "resident" PAM at different stages of differentiation; (3)\functional role of PAM including cytostatic and/or cytolytic capacities, regulatory function on natural killer cell activity, effects on humoral and cell-mediated immune responses and antineoplastic effects; (4)\mechanism of self-nonself recognition and autoreactivity; and (5)\factors influencing the development and differentiation of PAM and factors affecting their effector functions against target cells. Investigations on ontogenic development, differentiation and functions of PAM and regulatory mechanisms of their cytolytic effector functions may eventually lead to manipulation or control of the vital pulmonary defense system to confer on the host a better survival advantage.